Process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane

ABSTRACT

The present invention relates to a process for the enantiomeric enrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane with the aid of continuous countercurrent chromatography, which is also described as SMB chromatography (SMB=simulated moving bed).  
     In a further aspect, the invention relates to a process for the preparation of (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using the aforementioned process, which furthermore includes a racemization step.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a process for the enantiomericenrichment of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane withthe aid of continuous countercurrent chromatography, in particular, SMBchromatography (SMB=simulated moving bed). In a further aspect, theinvention relates to a process for the preparation of(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane using theaforementioned process, which furthermore includes a racemization step.

[0003] 2. Brief Description of the Prior Art

[0004] The enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (DOPP) are valuableintermediates for the preparation of quinolone- andnaphthyridone-carboxylic acid derivatives which, inter alia, have gainedgreat industrial importance as an active constituent of antibacterialagents and food additives (EP-A 550 903).

[0005] (1S,6R)-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane of theformula (Ia)

[0006] is, for example, a valuable intermediate for the preparation of(S,S)-2,8-diazabicyclo[4.3.0]nonane (IIa),

[0007] into which it can be converted by reduction of the carbonylgroups and debenzylation in a manner known per se (EP-A 350 733).(S,S)-2,8-Diazabicyclo[4.3.0]nonane is, for its part, used for thepreparation of the antibiotic moxifloxacin (INN,1-cyclo-propyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicacid, (III)) (EP-A 350 733):

[0008] (III)

[0009] The enantiomer(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (Ib)

[0010] is in turn a valuable intermediate for the preparation of(R,R)-2,8-diazabicyclo[4.3.0]nonane (IIb),

[0011] which can likewise be used for the preparation of very activeantibacterial agents (e.g. Interscience Conference on AntimicrobialAgents and Chemotherapy (ICMC), 1996, Abstr. No. F-001).

[0012] Processes for the enantiomeric enrichment ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane are known inprinciple.

[0013] Thus, for example, EP-A 550 903 discloses a process for theresolution of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane usingtartaric acid (Example A, Method IV and Example B, Method II a)). Theprocesses described there require, for the preparation of the(1S,6R)-enantiomer, repeated recrystallization of the diastereomericD-(−)-tartaric acid salts or reaction with L-(+)-tartaric acid andsubsequent reaction of the released mother liquor with D-(−)-tartaricacid and recrystallization. The enantiomeric excesses obtained are, at93.8% ee for the (1R,6S) enantiomer and 96.6% ee for the (1S,6R)enantiomer, inadequate with respect to the large number of operationsand the large amount of chiral auxiliary reagants and thus only oflimited suitability for industrial use. EP-A 1 192 153 discloses aprocess for the resolution ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, which, inter alia,employs (−)-2,3:4,6-di-O-iso-propylidene-2-keto-L-gulonic acid andcamphorsulphonic acid as chiral auxiliary reagents. However, here too,the amount of chiral auxiliary reagent needed and the large number ofworking steps restricts industrial use.

[0014] There was therefore the need for an efficient process for theenantiomeric enrichment ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in which theseparated enantiomers can be prepared on an industrial scale and in highabsolute and optical purity.

SUMMARY OF THE INVENTION

[0015] Surprisingly, a process for the enantiomeric enrichment ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane has now been found,which is characterized in that the enantiomeric enrichment is carriedout by continuous countercurrent chromatography.

[0016] The term “enantiomeric enrichment” is to be understood in thecontext of the invention in that a starting mixture, which contains thetwo enantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane,(1S,6R)- and (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane,is separated in such a manner that after the separation the enantiomersare present in higher optical purity than before the separation.

[0017] It may be pointed out that in the context of the invention, thedefinitions, parameters and explanations, which are general or mentionedin preferred ranges, can be combined with one another in any desiredmanner, i.e. also between the respective ranges and preferred ranges,and these combinations are also included in the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0018] For the process according to the invention, there is preferablyemployed a starting mixture which contains the enantiomers in a molarratio of 0.25:1 to 4:1 and preferably 0.8:1 to 1.25:1. Particularlypreferably, the starting mixture contains the racemic mixture of theenantiomers.

[0019] The optical purity is indicated below by the “enantiomericexcess” (ee), which is defined as:

ee[S]=(m[S]−m[R])/m(S+R)

[0020] where

[0021] ee(S) is the optical purity of the enantiomer S, m(S) is theamount of substance of the enantiomer $ and m(R) is the amount ofsubstance of the enantiomer R. It is customarily given in percentenantiomeric excess (% ee=ee/100).

[0022] cis-8-Benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane canadvantageously be obtained as a racemic mixture according to EP-A 350733 by nuclear hydrogenation of pyridine-2,3-dicarboxylic acidN-benzylimide. In this preparation method, in principle the transcompounds diastereomeric to the cis compounds can also be obtained asby-products. Furthermore, other organic by-products can also beproduced. It has surprisingly been found that the enantiomericenrichment according to the invention can also be carried out in thepresence of these by-products.

[0023] The invention therefore also comprises a process in which theenantiomeric enrichment ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is carried out inthe presence of the enantiomerictrans-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonanes and/or otherorganic by-products originating from the nuclear hydrogenation ofpyridine-2,3-dicarboxylic acid N-benzylimide.

[0024] Their mass content, based on the starting mixture employed forthe process according to the invention, which contains the enantiomersof cis-8-benzyl-7,9-dioxo-2,8-diaza-bicyclo[4.3.0]nonane, can be, forexample, 0.01 to 20%, and customarily 0.5 to 10%.

[0025] The principle of continuous countercurrent chromatography for theseparation of chiral compounds is known, for example, from M. Negawa andF. Shoji, J. Chrom. 590, 1992, pages 113-117. Suitable units forcarrying out continuous countercurrent chromatography such as, inparticular, SMB units are described, for example, in U.S. Pat. Nos.2,621,149; 2,985,589 and WO 92/16274 and are commercially obtainable.

[0026] Here, in general a stream of liquid moving in one direction andoptionally circulating is produced in an SMB unit by means of two ormore segments connected to one another, each segment having at least onecolumn filled with a chiral stationary phase and being provided in theflow direction at least with a liquid inlet and a liquid outlet and eachsegment having at least one inlet, via which a feedstream or an elutingagent can be fed to the optionally circulating stream of liquid, andfurthermore having at least one outlet, via which solutions of the moreweakly adsorbing compound (raffinate) or solutions of the more stronglyadsorbing compound (extract) can be removed from the optionallycirculating stream of liquid.

[0027] During operation of the SMB unit, the inlets and outlets areperiodically, but not necessarily simultaneously, connected further inthe direction of the flow of liquid, for example, via valves such as,for example, individual valves, multiway valves, valve blocks, flaps orrotation valves, such that apparently a countercurrent movement of thestream of liquid and stationary phase results. On account of this, theoptionally circulating stream of liquid can be divided into four zones,in which the individual segments can have different functions.

[0028] In Zone I, which is situated between the inlet for the elutingagent and the outlet for the extract, the more strongly adsorbingcompound is desorbed from the stationary phase.

[0029] In Zone II, which is situated between the outlet for the extractand the inlet for the feedstream, the more weakly adsorbing compound isdesorbed from the stationary phase.

[0030] In Zone III, which is situated between the inlet for thefeedstream and the outlet for the raffinate, the more strongly adsorbingcompound is adsorbed from the stationary phase.

[0031] In Zone IV, which is situated between the outlet for theraffinate and the inlet for the eluting agent, the more weakly adsorbingcompound is adsorbed from the stationary phase.

[0032] The zones can consist, for example, of one or more segments. Thenumber of segments per zone can change here, however. In special cases,it can be advantageous that a zone consists during a period of a liquidcompound, but not of segments or columns.

[0033] In certain cases, it can be advantageous to connect theindividual segments of the abovementioned device one after the other,not in an endless sequence (closed circulation), but in a series ofindividual segments having an inlet at the beginning of the segmentseries and an outlet at the end of the segment series. In this case, anopen circulation is referred to. Here, a part flow or the entire flow ofthe fluid, which is obtained via the outlet of the segment series, canbe recirculated to the inlet of the segment series directly or aftersuitable treatment.

[0034] Advantageous treatment methods are, for example, intermediatestorage, testing, distillation, removal of components by means ofmembrane processes, mixing, temperature-controlling and others.

[0035] In the context of the invention, the operation of an SMB unit asa closed circulation (with a circulating stream of liquid) is preferred.In the context of the invention, it is advantageous to employ a columnnumber from 4 to 24, preferably 5 to 12 and particularly preferably 5 to8.

[0036] Preferably, the columns are designed as cylindrical axial flowcolumns, which have a device for the dynamic compression of the chiralstationary phase in the axial direction. However, columns of otherstructural designs can also be employed.

[0037] The column diameter, i.e. the diameter of the packing of thechiral phase, can be, for example, 5 to 1500 mm, preferably 50 to 1200mm and particularly preferably 200 to 1200 mm. The column length, i.e.the length of the packing of the chiral phase in the flow direction, canbe, for example, 15 mm to 300 mm, preferably 40 mm to 170 mm.

[0038] It has proved advantageous to use columns whose packing has adiameter-length ratio of 0.25 to 20, particularly preferably 1 to 5.

[0039] Suitable chiral stationary phases are in particular those whichcontain the derivatives of polysaccharides, chiral polyacrylates orchiral crown ethers and which are optionally and preferably applied to asupport material.

[0040] Suitable chiral stationary phases are in particular those whichcontain derivatives of polysaccharides, optically activepoly(acryl)amides, optically active network polymers or chiral crownethers and which are optionally and preferably applied to a supportmaterial.

[0041] Such chiral stationary phases optionally applied to supportmaterials are disclosed, for example, in EP-A 358 129, EP-A 1 118 623,EP-A 978 498, EP-A 625 524, EP-A 527 239 and EP-A 671 975.

[0042] Suitable support materials are, for example, inorganic or organicsupport materials which are preferably porous. For use in the processaccording to the invention, porous inorganic support materials arepreferred.

[0043] Organic support materials are, for example, polymers such aspolystyrenes, polyacrylic acid derivatives or their copolymers.

[0044] Inorganic support materials are, for example, silicon compoundssuch as silicas, silica gels and silicic acids, silicates such aszeolites, aluminium compounds such as aluminas, aluminium oxides,aluminates, titanium compounds such as titanium dioxides and titanates,magnesium compounds such as magnesia, glasses, kaolin or apatites suchas, in particular, hydroxyapatite. Some of the support materialsmentioned can occur in various modifications, which are likewiseincluded.

[0045] Silica gels are particularly preferred as support materials.

[0046] The particles of the support material advantageously have anaverage diameter (based on the particle count) of 0.1 □m to 1 mm,preferably 1 μm to 500 μm.

[0047] Furthermore, the particles of the support material advantageouslyhave an average pore size of 10 Å to 50 □m.

[0048] Preferred polyacrylates are those which contain structural unitsof the formula (IV)

[0049] where in formula (IV)

[0050] R represents hydrogen or methyl,

[0051] R¹ represents an alkyl group having 1 to 18 C atoms or acycloalkyl group having 3 to 8 C atoms, each of which is optionallysubstituted by hydroxyl, halogen, alkoxy or cycloalkyl having up to 8carbon atoms, by an aryl group having up to 14 carbon atoms or by aheteroalkyl having 4 to 14 carbon atoms, which contains 1 or 2heteroatoms from the group consisting of nitrogen, oxygen and sulphur,where the aryl or heteroaryl groups mentioned are optionally substitutedby hydroxyl, halogen, alkyl or alkoxy in each case having 1 to 4 Catoms,

[0052] R³ represents hydrogen or together with R¹ represents a tri- ortetramethylene group,

[0053] X represents oxygen or an NR₄ group, in which R⁴ together with R²and the nitrogen atom form a 5- to 7-membered heterocyclic ring, whichis optionally substituted with a COO-alkyl group (1 to 4 C atoms) or by1 or 2 alkyl groups (in each case 1 to 4 C atoms), and

[0054] R² represents a bulky highly space-filling hydrocarbon radicalhaving up to 30 carbon atoms or a heteroaryl radical having 4 to 14carbon atoms, which contains 1 heteroatom from the group consisting ofnitrogen, oxygen or sulphur, where the hydrocarbon and heteroarylradicals mentioned are optionally substituted by halogen, hydroxyl,alkyl and/or alkoxy in each case having 1 to 8 carbon atoms, with theproviso that, if R² is a tertiary butyl group or X represents theradical NR⁴, R must be a methyl group.

[0055] For R¹, optionally substituted alkyl, cycloalkyl, aralkyl, aryland heteroaryl radicals which may preferably be mentioned are thefollowing radicals:

[0056] optionally substituted alkyl radicals the methyl, ethyl,i-propyl, n-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl,1-hydroxyethyl, 2-alkoxycarbonyl, 3-alkoxycarbonyl, 3-N-acylaminopropyl,4-N-acylaminobutyl or tert-butoxymethyl radical and the hydroxymethylradical;

[0057] optionally substituted cycloalkyl radicals the cyclohexyl radicaland the tetrahydronaphth-2-yl radical;

[0058] optionally substituted aralkyl radicals the benzyl radical and4-hydroxybenzyl radical;

[0059] optionally substituted aryl radicals the phenyl radical andnaphthyl radical; optionally substituted heteroaryl radical theindol-3-yl radical.

[0060] For R², highly space-filling radicals which may be mentioned are,for example:

[0061] tertiary alkyl radicals such as the tert-butyl radical, theneopentyl radical and the adamantyl radical;

[0062] alkyl radicals substituted in the 1-position by cycloalkylgroups, such as the cyclohexylmethyl radical or cyclohexylethyl radicalor cyclopropylmethyl radical;

[0063] optionally substituted cycloalkyl radicals such as the cyclohexylradical and the cyclohexyl radicals substituted by methyl groups ortert-butyl groups such as the 2- or 3-methylcyclohexyl radical, the4-tert-butyl radical and 2,6-di-tert-butyl-cyclohexyl radical or thedecahydronaphthyl radical;

[0064] aralkyl radicals such as the 1-phenylethyl radical and the2-phenylpropyl radical;

[0065] optionally substituted phenyl radicals such as the phenyl radicalor phenyl radicals substituted by C₁-C₄-alkyl groups such as the o-tolylradical, 2,6-xylyl radical, 4-tert-butyl radical and2,6-di-tert-butyl-phenyl radical; terpenyl radicals such as the menthyl,neomenthyl, bornyl, fenchyl and pinanyl radical.

[0066] Particularly advantageous is the use of optically active radicalsfor R², e.g. of the d- or l-1-phenylethyl radical or of the d- orl-methyl, d- or l-neomenthyl, d- or l-bornyl, d- or l-fenchyl radical orof the d- or l-pinanyl radical.

[0067] The polyacrylamides which contain the structural elements of theformula (VI) are preferably obtainable by polymerization of opticallyactive N-(meth)acryloylamino acid derivatives of the formula (V)

[0068] in which R, R¹, R² and R³ have the meaning mentioned under theformula (IV). Particularly preferred polyacrylates andN-(meth)acryloylamino acid derivatives of the formula (V) are derivedfrom optically active amino acids such as alanine, aminobutyric acid,valine, norvaline, leucine, isoleucine, terleucine, phenylglycine,phenylalanine, naphthylalanine, cyclohexylglycine, cyclohexylalanine,tyrosine, tryptophan, threonine, serine, aspartic acid, glutamic acid,ornithine, lysine or proline.

[0069] Very particularly preferred N-(meth)acryloylamino acidderivatives of the formula (I) are: N-(meth)acryloylalanine menthylester, N-(meth) acryloylalanine bornyl ester, N-(meth)acryloylalaninefenchyl ester, N-(meth)acryloylphenyl alanine methyl ester,N-methacryloyl-phenylglycine tert-butyl ester, N-methacryloyl-leucinetert-butyl ester, N-methacryloylphenylalanine tert-butyl ester,N-(meth)acryloyl-valine trans-4-tert-butylcyclohexyl ester,N-methacryloyl-N′-tert-butoxycarbonyl-lysine tert-butyl ester,N-methacryloyl-isoleucine tert-butyl ester, N-methacryloylvalinetert-butyl ester, N-methacryloyl-cyclohexylalanine tert-butyl ester,N(meth)-acryloyl-alanine 2-decahydronaphthyl ester,N-methacryloyl-alanine methylamide, N-methacryloyl-phenyl-alaninemethylamide and N-methacryloylphenyl-alanine 1-phenylethylamide.

[0070] The optically active poly(meth)acrylamides containing thestructural units of the formula (IV) are preferably present in the formof cross-linked insoluble but swellable polymers or in a form preferablybound to inorganic support materials.

[0071] The cross-linked polymers are furthermore preferably present inthe form of finely divided beads having a particle diameter of 5 to 200μm. They can be prepared in a manner known per se by suspensionpolymerization of the optically active (meth)acrylamide monomers of theformula (VI) with 0.5 to 50 mol %, preferably 1 to 20 mol %,particularly preferably 3 to 15 mol %, (based on the total amount(moles) of the monomers employed) of a suitable cross-linker.

[0072] Preferred network polymers are those which are derived fromoptically active diamines, dicarboxylic acids, diols orhydroxycarboxylic acids. Particularly preferred network polymers arethose which are derived from tartaric acid derivatives which aredisclosed in EP-A 671 975.

[0073] Preferred crown ethers are those of the general formula (VI)

[0074] in each case in the R,R or S,S form, having an optical purity ofat least 95% ee, preferably at least 98% ee and particularly preferablyat least 99% ee

[0075] and in which D and E independently of one another, but preferablyidentically, represent hydrogen, C₁-C₆-alkyl, C₆-C₁₀-aryl orC₇-C₁₁-arylalkyl and

[0076] R⁴ and R⁵ in each case independently of one another, butpreferably identically, represent radicals which are selected from thegroup consisting of C₁-C₃₀-alkyl or C₆-C₁₀-aryl, where the number ofradicals R⁴ and R⁵ on the naphthyl unit is in each case zero, one, twoor three, but preferably in each case identically zero or one, where ineach case substitution in the 6,6′-position is preferred and the sum ofn+m is 3 to 10, preferably 4 to 8 and particularly preferably 5 or 6.

[0077] Chiral crown ethers of the formula (VI) in which D and E in eachcase identically represent phenyl, n+m=5 and the number of the radicalsR⁴ and R⁵ is zero are particularly preferred.

[0078] As stationary chiral phases which contain chiral crown ethers,those are preferred which have crown ethers of the formula (VI)including the preferred ranges mentioned and are applied to silica gel.Such chiral phases are commercially available, for example, under thename Crownpak CR (+,−)® from Daicel.

[0079] Preferred derivatives of polysaccharides are those which arederived from natural or synthetic glucans, mannans, galactans, fructans,xylans or chitosans.

[0080] Preferably, derivatives of those polysaccharides are employed,which are derived from polysaccharides which have a regular mode ofbonding in the chain. These are, for example, □-1,3-glucans such as inparticular curdlan and schizophyllan, □-1,4-glucans such as inparticular cellulose, □-1,6-glucans such as in particular pustulan,□-1,2-glucans such as in particular crown gall polysaccharides,□-1,3-glucans, □-1,4-glucans such as in particular amylose andamylopectin or starches, □-1,6-glucans such as in particular dextransand cyclodextrans, □-1,6-mannans, □-1,4-mannans, □-1,4-galactans,□-1,2-fructans such as in particular inulin, □-2,6-fructans such as inparticular levan, □-1,3-xylans, □-1,4-xylans, □-1,4-chitosans,□-1,4-N-acetylchitosans such as in particular chitin. Particularlypreferably, derivatives of those polysaccharides are employed which arederived from cellulose, chitin and amylose.

[0081] The average degree of polymerization of the polysaccharide(number average) can, for example, be and preferably is 5 to 500monosaccharide units but in principle is not restricted upwardly.

[0082] The term “derivative of polysaccharides” is to be understood asmeaning polysaccharides in which the hydrogen atoms of the hydroxygroups or in each case one hydrogen atom of the amino groups, butpreferably the hydrogen atoms of the hydroxy groups, are substituted atleast partially by radicals containing up to 30 carbon atoms.Preferably, at least 30%, particularly preferably at least 50% and veryparticularly preferably at least 80% of the hydrogen atoms of hydroxygroups or in each case of a hydrogen atom of amino groups aresubstituted.

[0083] Preferred radicals having up to 30 carbon atoms are those of theformula (VIIa),

R⁶—  (VIIa),

[0084] in which R⁶ represents C₄-C₁₄-aryl, or those of the formula(VIIb)

R⁷-A-CO—  (VIIb),

[0085] in which R⁷ represents C₄-C₁₄-aryl and at the same time A isabsent or represents C₁-C₄-alkanediyl or C₂-C₄-alkenediyl or R⁷represents C₁-C₄alkyl and at the same time A is absent, or those of theformula (VIIc)

R⁸—B—NHCO—  (VIIc),

[0086] in which R⁸ represents C₄-C₁₄-aryl and B is absent or representsC₁-C₄alkanediyl.

[0087] C₄-C₁₄-Aryl here represents, for example and preferably,carbocyclic aromatic radicals or heteroaromatic radicals, which containno, one or two heteroatoms per cycle, in the entire heteroaromaticradical at least, however, one heteroatom, which are selected from thegroup consisting of nitrogen, sulphur and oxygen. Furthermore, thecarbocyclic aromatic radicals or heteroaromatic radicals can besubstituted with one, two, three, four or five substituents per cycle,which in each case independently of one another are selected for exampleand preferably from the group consisting of C₁-C₄-alkyl, nitro, cyano,O-(C₁-C₄-alkyl), fluorine, chlorine, bromine, tri(C₁-C₄-alkyl)silyl.

[0088] C₁-C₄-Alkyl here in each case independently represents astraight-chain, branched or unbranched C₁-C₄-alkyl radical such as, forexample, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl andtert-butyl. C₁-C₄-Alkanediyl here in each case independently representsa straight-chain, branched or unbranched C₁-C₄-alkanediyl radical suchas, for example, methylene, (S)-1,1-ethylene, (R)-1,1-ethylene,1,2-propanediyl and 1,3-propanediyl.

[0089] C₂-C₄-Alkenediyl here in each case independently represents astraight-chain, branched or unbranched C₂-C₄-alkenediyl radical such as,for example, ethenyl, 1,2-propenyl and 1,3-propenyl.

[0090] In formula (VIIa), R⁶ preferably represents phenyl, which issubstituted with no, one or two radicals, which in each caseindependently are selected from the group consisting of methyl, nitro,chlorine, bromine, tri(C₁-C₄-alkyl)silyl.

[0091] In formula (VIIb), R⁷ and A together preferably represent methyl,2-phenylethenyl, phenyl or p-tolyl.

[0092] In formula (VIIc), R⁸ and B together preferably represent (S) or(R)-phenylethyl, phenyl, 3,5-dimethylphenyl, p-tolyl and p-chlorophenyl,where 3,5-dimethylphenyl is even further preferred.

[0093] Stationary chiral phases in the context of the invention arepreferably those which have chiral crown ethers of the formula (VI)including the preferred ranges mentioned and are applied to silica gel.Such chiral phases are commercially available, for example, under thename Crownpak CR (+,−)® from Daicel.

[0094] Furthermore, as stationary chiral phases in the context of theinvention those are preferred which have derivatives of polysaccharidesincluding the preferred ranges mentioned and are applied to silica gel.Such chiral phases are commercially available, for example, under thename Chiralpak® (AD, AS)™ or Chiralcel® (OD, OJ, OA, OB, OC, OF, OG,OK)™ from Daicel.

[0095] Particularly preferably, stationary chiral phases used in thecontext of the invention are those are which contain amylosetris(3,5-dimethylphenylphenylcarbamate), amylosetris-[(S)-□-methylbenzylcarbamate], cellulosetris(3,5-dimethylphenylcarbamate), cellulose tris(4-methylbenzoate) orcellulose tris(4-chlorphenylcarbamate) and are applied to silica gel(e.g., obtainable under the name Chiralpak® (AD, AS)™ or Chiralcel (OD,OJ, OF)™ from Daicel).

[0096] Very particularly preferred stationary chiral phases in thecontext of the invention are those which contain amylosetris(3,5-dimethylphenylcarbamate) or cellulosetris(3,5-dimethylphenylcarbamate) and are applied to silica gel (e.g.obtainable under the name Chiralpak® (AD)™ or Chiralcel® (OD)™ fromDaicel), where as stationary chiral phases those are even furtherpreferred which contain amylose tris(3,5-dimethylphenylcarbamate) andare applied to silica gel [Chiralpak® (AD)™].

[0097] The starting mixture employed for the separation of enantiomers,which contains the enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, is supplied to thecirculating stream of liquid dissolved in a solvent as a “feedstream”.

[0098] The proportion of the starting mixture in the feedstream can be,for example, 1 to 35 mass %, preferably 5 to 30 mass % and particularlypreferably 15 to 30 mass %.

[0099] Suitable solvents are organic solvents. These are, for exampleand preferably, aliphatic hydrocarbons having 6 to 12 carbon atoms suchas preferably methyl-cyclohexane, cyclohexane, n-hexane and n-heptane,ethers such as preferably tetrahydrofuran, aliphatic alcohols having 1to 6 carbon atoms such as preferably methanol, ethanol and isopropanol,nitrites such as preferably acetonitrile, benzonitrile and benzylnitrites or mixtures of such solvents.

[0100] n-Hexane, n-heptane, isopropanol and acetonitrile or mixturesthereof are particularly preferred, acetonitrile being even furtherpreferred.

[0101] An eluting agent is furthermore supplied to the optionallycirculating stream of liquid. The eluting agent is more advantageouslyan organic solvent, the abovementioned details including the preferredranges applying in the same way. Particularly preferably, the samesolvents are employed for the feedstream and the eluting agent.

[0102] If mixtures of solvents are employed, it is furthermore possibleto change the composition during the addition of the eluting agent,which can take place, for example, at intervals or continuously in theform of a gradient.

[0103] In the context of the invention, it is preferred, however, towork at constant composition of the solvent. Even further preferred isthe use of only one solvent.

[0104] Advantageously, organic solvents are used which have a watercontent of 3 mass % or less, preferably 0.3 mass % or less andparticularly preferably 0.03 mass % or less.

[0105] The pressure during the addition of the feedstream and of theeluting agent can be, for example, 0.5 bar to 100 bar, 1 bar to 60 barbeing preferred.

[0106] The temperature during the enantiomeric enrichment can be, forexample, 0 to 80° C., preferably 10 to 40° C., particularly preferably18 to 32° C. and very particularly preferably 20 to 28° C.

[0107] The raffinate and the extract can then be removed from the SMBunit, these fractions in each case containing an enriched enantiomer ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, it being possiblefor the enriched enantiomers to be obtained by removal of the solvent,for example by evaporation.

[0108] In the manner according to the invention, the enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in particular(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, can beobtained, for example, with optical purities of 70% ee or more,preferably 85% ee or more, particularly preferably 90% ee or more andvery particularly preferably 95% ee or more.

[0109] In the manner according to the invention, the enantiomer of theraffinate, preferably(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, can beobtained, for example, with absolute purities of 90% or more, preferably95% or more and particularly preferably 98% or more.

[0110] Furthermore, in the manner according to the invention, theenantiomer of the extract, preferably(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, can beobtained, for example, with absolute purities of 85% or more, preferably90% or more and particularly preferably 95% or more.

[0111] The yields, based on the maximally obtainable amount of theenantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, inparticular (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, canbe 60% or more, preferably 80% or more and particularly preferably 95%or more.

[0112] It is a particular characteristic of the process according to theinvention that the enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in particular(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, can beobtained in optical purities of 95% ee or more with yields based on themaximally obtainable amount of the enantiomer of over 95%.

[0113] Furthermore, the enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in particular(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, can beobtained in optical purities of 90% ee or more with a productivity ofover 0.2 kg, preferably over 0.8 kg and particularly preferably over 3.0kg, per kg of chiral stationary phase per day [kg/(kg_(CSP)·d)].

[0114] If for a subsequent step only one enantiomer is of interest, itis advantageous to racemize the enriched undesired enantiomer and to addit again to the continuous countercurrent chromatography.

[0115] In a preferred embodiment,(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is obtainedfrom the raffinate and the enantiomer(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is racemizedand added again to the continuous countercurrent chromatography.

[0116] The racemization is known in principle from EP-A 1067 129 andcarried out by addition of base.

[0117] In this case, for the racemization, for example, pure(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane or mixtures canbe employed which contain, for example, over 70% by weight, preferablyover 85% by weight, of(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane. Making up to100%, these mixtures can contain, for example,(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane.

[0118] Furthermore, it is possible and preferred to employ theenantiomer to be racemized, preferably(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, directly inthe form of the raffinate or extract solution from the enantiomericenrichment. Customarily,(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is obtained inthe form of the extract solution.

[0119] Optionally, the raffinate or extract solution can be concentratedby evaporation of solvent.

[0120] Suitable bases for the racemization are, for example, alkoxidesof the formula (VIII),

MOR⁹  (VIII),

[0121] in which

[0122] M represents lithium, sodium or potassium, preferably sodium orpotassium and

[0123] R⁹ represents a straight-chain or branched C₁-C₆-alkyl,preferably methyl or tert-butyl.

[0124] Preferred individual compounds of the formula (VIII) are sodiummethoxide, sodium tert-butoxide and potassium tert-butoxide. Potassiumtert-butoxide is particularly preferred.

[0125] Preferably, the base is employed in an amount of from 1 to 20 molbased on the amount ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane to be racemized.

[0126] The alkoxides can be added in solid form or dissolved in asolvent. Suitable solvents are, for example, alcohols and aproticsolvents, for example the alcohol which corresponds to the alkoxideemployed in each case, and straight-chain, branched and cyclic ethers aswell as aromatic hydrocarbons. Individual examples of aprotic solventsare: methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene andxylene. Preferred alkoxide solutions are: potassium tert-butoxide intert-butanol and in tetrahydrofuran and sodium methoxide in methanol.

[0127] In a preferred embodiment, the alkoxide is added to the solventwhich serves as the eluting agent in the chromatographic separation.

[0128] The racemization can be carried out, for example, at temperaturesbetween −10 and 40° C.

[0129] The racemization according to the invention is in generalcomplete after, at the latest, 5 hours. Under suitable reactionconditions (e.g. appropriate choice of the base, of the solvent and ofthe temperature), the reaction time necessary can be significantlyshorter and can be, for example, 15 minutes or even less.

[0130] The reaction mixture present after the racemization can be workedup such that the base employed is firstly neutralized, e.g. by additionof an organic acid, e.g. of a C₁-C₆-carboxylic acid, of a mineral acid,e.g. sulphuric acid or phosphoric acid, of carbonic acid or of an acidicion exchanger. The amount of the acid or of the acidic ion exchanger canbe, for example, 0.9 to 1.1 equivalents per equivalent of base employed.Preferably, this amount is 0.97 to 1.03 equivalents per equivalent ofbase employed, in particular the acid or the acidic ion exchanger isemployed in equivalent amount, based on the base employed. Afterwards,the solvent can be removed, e.g. by distillation, optionally underreduced pressure. A racemization mixture remains which contains theenantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonanes ina molar ratio of 1:1 to 1.5:1, preferably 1:1 to 1.1:1, it of coursebeing possible for only that enantiomer to be present in an excess whichwas employed in enriched form for the racemization.

[0131] If before, during or after implementation, solvents are removedwhich were employed as eluting agents, these can be employed again forthe process according to the invention.

[0132] The racemization mixture can then either be stored or added againto the enantiomeric enrichment. This process course, enantiomericenrichment, racemization, enantiomeric enrichment, can be repeated asoften as desired, optionally with continuous readdition of startingmixture, so that, in the manner according to the invention, finally, forexample, the racemic mixture ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonanes obtained in thenuclear hydrogenation of pyridine-2,3-dicarboxylic acid N-benzylimidecan be converted completely into an enriched enantiomer, preferably(1S,6R)8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane with highabsolute and optical purity.

[0133] The enriched enantiomers(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane obtainable inthe manner according to the invention are suitable, in particular, in aprocess for the preparation of antibacterial agents and food additives.

[0134] Furthermore, the enriched enantiomer(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane obtainable inthe manner according to the invention is suitable for the preparation of(S,S)-2,8-diazabicyclo[4.3.0]nonane and moxifloxacin (INN,1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicacid, the enriched enantiomer(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane for thepreparation of (R,R)-2,8-diazabicyclo[4.3.0]nonane.

[0135] The process according to the invention is distinguished in that,in a continuous process,(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane can be obtainedin high purity, optical purity and high yield with unexpectedproductivity. By means of a downstream racemization and recycling to theseparation process, it is furthermore possible in a particularlyadvantageous manner to obtain a single target enantiomer, in particular(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, in a veryhighly efficient manner.

EXAMPLES Example 1

[0136] A continuously operating countercurrent chromatography unit fromNovaSep, France, was employed (type: LICOSEP 8-200). Characteristiccomponents of the unit are 8 axial flow columns (diameter in each case200 mm) having a device for the dynamic axial compression of thestationary phase.

[0137] All external feeds and drains are in each case fed to specificsites or drained by means of appropriate connections, which correspondwith the recirculating concentration profile. The following quantitativeflows are established: Zone I:   500 l/h Zone II: 260.0 l/h Zone III:274.5 l/h Zone IV: 200.0 l/h Eluting agent:   300 l/h (acetonitrile,water content: <300 ppm) Feedstream:  14.5 l/h with 199.4 mg ofrac-DOPP/ml (solvent: acetonitrile, water content <300 ppm) Raffinate: 74.5 l/h of (1S,6R)-8-benzyl-7,9-dioxo-2,8- diaza-bicyclo[4.3.0]nonanein acetonitrile Extract: 240.0 l/h h of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diaza-bicyclo[4.3.0]nonane in acetonitrile Cycle time:  0.72 minTemperature:   25° C. Chiral stationary phase: Chiralpak ® AD ™, 20 μm

[0138] The compositions of the feedstream and of the extract arespecified in Table 1 below. The yield is quantitative. TABLE 1 ExtractRaffinate Productivity % ee %* % ee %* kg_(rac)/kg_(CSP)/d 95.6 96.498.4 98.8 5.42

Example 2

[0139] A continuously operating countercurrent chromatography unit fromNovaSep, France, was employed (type: LICOSEP 8-200). Characteristiccomponents of the unit are 7 axial flow columns (diameter in each case200 mm) having a device for the dynamic axial compression of thestationary phase, which used the configuration 2:2:2:1(Zone1:Zone2:Zone3:Zone4).

[0140] All external feeds and drains are fed to specific sites ordrained by means of appropriate connections, which correspond with therecirculating concentration profile. The following quantitative streamswere established: Zone I:   500 l/h Zone II: 286.5 l/h Zone III: 297.0l/h Zone IV: 200.0 l/h Eluting agent:   300 l/h (acetonitrile, watercontent: <300 ppm) Feedstream:  10.5 l/h with 202.7 mg of rac-DOPP/ml(solvent: acetonitrile, water content <300 ppm) Raffinate:   97 l/h of(1S,6R)-8-benzyl-7,9-dioxo-2,8- diaza-bicyclol[4.3.0]nonane inacetonitrile Extract: 213.5 l/h of (1R,6S)-8-benzyl-7,9-dioxo-2,8-diaza-bicyclo[4.3.0]nonane in acetonitrile Cycle time:  0.69 minTemperature:   27° C. Chiral stationary phase: Chiralpak ® AD ™, 20 μm

[0141] The compositions of the feedstream and of the extract arespecified in Table 2 below. The yield is quantitative. TABLE 2 ExtractRaffinate Productivity % ee %* % ee %* kg_(rac)/kg_(CSP)/d >99.996.3 >99.9 98.9 4.56

[0142] Although the invention has been described in detail in theforegoing for the purpose of illustration, it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those skilled in the art without departing from the spiritand scope of the invention except as it may be limited by the claims.

What is claimed is:
 1. Process for the enantiomeric enrichment ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane, comprisingcarrying out the enantiomeric enrichment by continuous countercurrentchromatography.
 2. Process according to claim 1, characterized in thatthe enantiomeric enrichment is carried out with the aid of an SMB unit.3. Process according to claim 2, characterized in that a stream ofliquid moving in one direction and optionally circulating is produced inthe SMB unit by means of two or more segments connected to one another,each segment having at least one column filled with a chiral stationaryphase and being provided in the flow direction at least with a liquidinlet and a liquid outlet and each segment having at least one inlet,via which a feedstream or an eluting agent can be fed to the optionallycirculating stream of liquid, furthermore having at least one outlet,via which solutions of the more weakly adsorbing compound (raffinate) orsolutions of the more strongly adsorbing compound (extract) can beremoved from the optionally circulating stream of liquid.
 4. Processaccording to claim 2, characterized in that the SMB unit has a columnnumber of 4 to
 24. 5. Process according to claim 2, characterized inthat the SMB unit contains columns which are designed as cylindricalaxial flow columns and have a device for dynamic compression.
 6. Processaccording to claim 2, characterized in that the SMB unit containscolumns which have a column diameter of 5 to 1500 mm.
 7. Processaccording to claim 2, characterized in that the SMB unit containscolumns which have a column length of 15 mm to 300 mm.
 8. Processaccording to claim 3, characterized in that a closed circulation with acirculating stream of liquid is produced in the SMB unit.
 9. Processaccording to claim 1, characterized in that, for the enantiomericenrichment, a starting mixture is employed which contains theenantiomers of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane in amolar ratio of 0.25:1 to 4:1.
 10. Process according to claim 1,characterized in that thecis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is obtained bynuclear hydrogenation of pyridine-2,3-dicarboxylic acid-N-benzylimide.11. Process according to claim 10, characterized in that theenantiomeric enrichment is carried out in the presence oftrans-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane or itsenantiomers and/or other organic by-products originating from thenuclear hydrogenation of pyridine-2,3-di-carboxylic acid N-benzylimide.12. Process according to claim 1, characterized in that, for theenantiomeric enrichment, columns are employed which, as a chiralstationary phase, contain polysaccharides, chiral polyacrylates, orchiral crown ethers, which are optionally applied to a support material.13. Process according to claim 1, characterized in that, as chiralstationary phases, those are used which contain amylosetris(3,5-dimethylphenylcarbamate), amylosetris[(S)-□-methylbenzylcarbamate], cellulosetris(3,5-dimethylphenylcarbamate), cellulose tris(4-methylbenzoate) orcellulose tris(4-chlorphenylcarbamate) and are applied to silica gel.14. Process according to claim 12, characterized in that, as a chiralstationary phase, those are used which contain amylosetris(3,5-dimethylphenylcarbamate) or cellulose tris(3,5-dimethylphenylcarbamate) and are applied to silica gel.
 15. Process according toclaim 1, characterized in that the, solvents employed are aliphatichydrocarbons having 6 to 12 carbon atoms, ethers, aliphatic alcoholshaving 1 to 6 carbon atoms, nitrites or mixtures of such solvents. 16.Process according to claim 1, characterized in that the solvent employedis acetonitrile.
 17. Process according to claim 1, characterized in thatthe solvents used are those which have a water content of 3 mass % orless.
 18. Process according to claim 2, characterized in that thepressure during the feed of the feedstream and of the eluting agent is0.5 bar to 100 bar.
 19. Process according to claim 1, characterized inthat the temperature during the enantiomeric enrichment is 0 to 80° C.20. Process according to claim 1, characterized in that the enantiomersof cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane having opticalpurities of 70% ee or more are obtained.
 21. Process according to claim1, characterized in that the enantiomers ofcis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonanes are obtained withoptical purities of 90% ee or more having a productivity of over 0.2 kgper kg of chiral stationary phase per day.
 22. Process according toclaim 1, characterized in that the enriched, undesired enantiomer isracemized.
 23. Process according to claim 22, characterized in that theenriched undesired enantiomer is racemized and fed again to thecontinuous countercurrent chromatography.
 24. Process according to claim22, characterized in that(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane is obtained andthe enantiomer (1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonaneis racemized and fed again to the continuous countercurrentchromatography.
 25. A process for the production of antibaccterialagents and food additives comprising incorporating the enrichedenantiomers (1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane and(1R,6S)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane preparedaccording to claim
 1. 26. A process for preparing(S,S)-2,8-diazabicyclo[4.3.0]nonane and1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluor-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylicacid comprising providing(1S,6R)-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane for thepreparation.